Minimal Risk of Hepatocellular Carcinoma in Noncirrhotic Budd-Chiari Syndrome: A Three-Decade Population-Based Study
Authors: Axel Wester, Fredrik Åberg, Rupesh Rajani, Hannes Hagström
Journal: Clinical Gastroenterology and Hepatology (2022)

Budd-Chiari syndrome (BCS) is a rare condition characterized by hepatic venous outflow obstruction, usually caused by thrombosis. The pathophysiological consequences include sinusoidal congestion, hepatocellular ischemia, and risk for cirrhosis. Additionally, benign liver nodules are frequently found during follow-up after BCS, but may be difficult to distinguish from hepatocellular carcinoma (HCC). The cumulative incidence of HCC in BCS has been estimated at 4% after a median follow-up of 5 years, but this is based on a single-center study in a tertiary setting, which might introduce selection bias.1Moucari R. et al.Gut. 2008; 57: 828-835Crossref PubMed Scopus (124) Google Scholar Screening for HCC is recommended in all patients with BCS in the guidelines from the European Association for the Study of the Liver.2European Association for the Study of the Liver.J Hepatol. 2016; 64: 179-202PubMed Scopus (0) Google Scholar Similar recommendations are made by the American Association for the Study of Liver Diseases and the American College of Gastroenterology,3Simonetto D.A. et al.Am J Gastroenterol. 2020; 115: 18-40Crossref PubMed Scopus (57) Google Scholar,4Northup P.G. et al.Hepatology. 2021; 73: 366-413Crossref PubMed Scopus (121) Google Scholar but the level of evidence for these recommendations is low. Additionally, because of the low incidence of BCS, studies on this topic have included few patients or have been restricted to specialized tertiary centers. The risk of HCC in an unselected nationwide cohort of patients with BCS is therefore unknown.Recently, we developed a cohort of all patients with BCS in Sweden between 1987 and 2016 and estimated their mortality rate to be more than 3-fold higher than for control subjects from the general population who were matched for age, sex, and municipality.5Hagstrom H. et al.Scand J Gastroenterol. 2022; : 1-6Google Scholar,6Åberg F. et al.Clin Gastroenterol Hepatol. 2022; Google Scholar BCS was defined by International Classification of Disease (ICD) codes in the Swedish National Patient Registry (ICD-9: 453A and ICD-10: I82.0). This registry contains diagnostic codes from all hospital discharges in Sweden since 1964 and from outpatient visits in specialized care since 2001.7Bengtsson B. et al.Scand J Gastroenterol. 2020; 55: 1205-1210Crossref PubMed Scopus (23) Google Scholar By manual chart review, a diagnosis of BCS in the registry had a positive predictive value of 93%.6Åberg F. et al.Clin Gastroenterol Hepatol. 2022; Google ScholarHere, we defined the start of follow-up (baseline) as 90 days after the date of BCS and excluded patients and control subjects meeting any of the following criteria before baseline: emigration from Sweden, death, liver transplantation, or previous HCC (Supplementary Figure 1). The lag period was introduced to exclude cases where HCC was likely present already at the date of BCS diagnosis. The primary outcome was incident HCC. The positive predictive value of a diagnosis of HCC in the National Patient Registry has been estimated to be 91% if combined with a chronic liver disease (eg, BCS).7Bengtsson B. et al.Scand J Gastroenterol. 2020; 55: 1205-1210Crossref PubMed Scopus (23) Google Scholar Because we suspected the incidence of HCC to be lower than previously reported, we defined HCC by ICD codes in the National Patient Registry, the Swedish Cancer Registry, and the Causes of Death Registry, to maximize the sensitivity (Supplementary Table 1). Follow-up was until the date of HCC, death, emigration from Sweden, liver transplantation, or December 31, 2016. The cumulative incidence of HCC was calculated while accounting for the competing risks of non-HCC death or liver transplantation (Supplementary Table 1).8Austin P.C. et al.Circulation. 2016; 133: 601-609Crossref PubMed Scopus (1015) Google Scholar Moreover, we analyzed the risk of HCC stratified for the presence of cirrhosis at baseline (defined as ICD coding for cirrhosis, ascites, esophageal varices, hepatorenal syndrome, or liver encephalopathy) (Supplementary Table 1). The study was approved by the regional ethics committee of Stockholm (protocol number 2017/1019-31/1).We identified 406 patients with BCS and 3883 matched control subjects who were followed for a median of 5.4 (interquartile range, 2.0–11.0) and 9.0 years (interquartile range, 4.1–14.1), respectively. The median age at baseline was 56 years and 42% were men in both groups. During follow-up, 7 persons developed HCC: 3 control subjects (0.08%) and 4 patients with BCS (0.99%). Patients with BCS had a higher incidence of HCC (1.3 per 1000 person-years; 95% confidence interval [CI], 0.5–3.6) compared with control subjects (0.1 per 1000 person-years; 95% CI, 0.0–0.2), corresponding to a hazard ratio of 11.9 (95% CI, 2.6–53.3). The cumulative incidence of HCC in patients with BCS was 0.57% at 5 years and 2.31% at 20 years (Table 1). In the 4 patients who developed HCC, the median age was 44 years at baseline (range, 39–61) and 56 years at the time of HCC (range, 50–63). The median time to HCC for these 4 patients was 7.5 years (range, 2.1–19.7). Of the 4 patients, 3 had cirrhosis at baseline and all developed cirrhosis before HCC. Among 77 (19.0%) patients with BCS who had a previous record of cirrhosis before baseline, the incidence of HCC was 7.3 per 1000 person-years (95% CI, 2.4–22.7) and the cumulative incidence 3.11% (95% CI, 0.58–9.64) at 5 years and 7.58% (95% CI, 1.56–20.18) at 20 years. In 329 (81.0%) patients with BCS without cirrhosis at baseline, 1 developed HCC after 19.7 years of follow-up, corresponding to an incidence of 0.4 per 1000 person-years (95% CI, 0.1–2.7) and a cumulative incidence at 20 years of 1.39% (95% CI, 0.12–6.58) (Table 1).Table 1Total Numbers and Cumulative Incidence of Hepatocellular Carcinoma for all Patients With BCS, Patients With BCS With or Without Coexisting Cirrhosis, and Control Subjects, at 1, 5, 10, and 20 YearsTime after baselineAll patients with BCS (n = 406)Patients with BCS and cirrhosis (n = 77)Patients with BCS and no cirrhosis (n = 329)Control subjects (n = 3883)Events, n (%)Cumulative incidence (95% CI)Events, n (%)Cumulative incidence (95% CI)Events, n (%)Cumulative incidence (95% CI)Events, n (%)Cumulative incidence (95% CI)1 y0 (0.00)—0 (0.00)—0 (0.00)—1 (0.03)0.03% (0.00–0.15)5 y2 (0.49)0.57% (0.12–1.92)2 (2.60)3.11% (0.58–9.64)0 (0.00)—2 (0.05)0.06% (0.01–0.21)10 y2 (0.49)0.57% (0.12–1.92)2 (2.60)3.11% (0.58–9.64)0 (0.00)—3 (0.08)0.10% (0.03–0.27)20 y4 (0.99)2.31% (0.58–6.33)3 (3.90)7.58% (1.56–20.18)1 (0.30)1.39% (0.12–6.58)3 (0.08)0.10% (0.03–0.27)BCS, Budd-Chiari syndrome; CI, confidence interval. Open table in a new tab The positive predictive values of our exposure and outcome definitions are high,6Åberg F. et al.Clin Gastroenterol Hepatol. 2022; Google Scholar,7Bengtsson B. et al.Scand J Gastroenterol. 2020; 55: 1205-1210Crossref PubMed Scopus (23) Google Scholar but misclassification bias can still exist. However, this limitation is more likely to lead to false-positive findings of HCC, which is why an overestimation of the risk of HCC in our analysis cannot be ruled out.Our data show that HCC is rare in unselected patients with BCS, with an absolute risk of 0.6% 5 years after BCS diagnosis and 2.3% at 20 years, corresponding to an excess risk at 20 years of 2.2% compared with the general population. In contrast, biopsy-proven alcohol-related liver disease and nonalcoholic fatty liver disease are associated with 20-year excess risks of 4.9% and 2.1%, respectively.9Hagstrom H. et al.Clin Gastroenterol Hepatol. 2022; 20: 918-929Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar,10Simon T.G. et al.Hepatology. 2021; 74: 2410-2423Crossref PubMed Scopus (29) Google Scholar However, these patients are not recommended universal screening for HCC, unless cirrhosis is present. Cirrhosis preceded HCC in all patients with BCS and no patient developed HCC before 50 years of age.In conclusion, screening for HCC may be considered in patients with BCS and concomitant cirrhosis aged 50 or more, but may not be motivated in other patients. Budd-Chiari syndrome (BCS) is a rare condition characterized by hepatic venous outflow obstruction, usually caused by thrombosis. The pathophysiological consequences include sinusoidal congestion, hepatocellular ischemia, and risk for cirrhosis. Additionally, benign liver nodules are frequently found during follow-up after BCS, but may be difficult to distinguish from hepatocellular carcinoma (HCC). The cumulative incidence of HCC in BCS has been estimated at 4% after a median follow-up of 5 years, but this is based on a single-center study in a tertiary setting, which might introduce selection bias.1Moucari R. et al.Gut. 2008; 57: 828-835Crossref PubMed Scopus (124) Google Scholar Screening for HCC is recommended in all patients with BCS in the guidelines from the European Association for the Study of the Liver.2European Association for the Study of the Liver.J Hepatol. 2016; 64: 179-202PubMed Scopus (0) Google Scholar Similar recommendations are made by the American Association for the Study of Liver Diseases and the American College of Gastroenterology,3Simonetto D.A. et al.Am J Gastroenterol. 2020; 115: 18-40Crossref PubMed Scopus (57) Google Scholar,4Northup P.G. et al.Hepatology. 2021; 73: 366-413Crossref PubMed Scopus (121) Google Scholar but the level of evidence for these recommendations is low. Additionally, because of the low incidence of BCS, studies on this topic have included few patients or have been restricted to specialized tertiary centers. The risk of HCC in an unselected nationwide cohort of patients with BCS is therefore unknown. Recently, we developed a cohort of all patients with BCS in Sweden between 1987 and 2016 and estimated their mortality rate to be more than 3-fold higher than for control subjects from the general population who were matched for age, sex, and municipality.5Hagstrom H. et al.Scand J Gastroenterol. 2022; : 1-6Google Scholar,6Åberg F. et al.Clin Gastroenterol Hepatol. 2022; Google Scholar BCS was defined by International Classification of Disease (ICD) codes in the Swedish National Patient Registry (ICD-9: 453A and ICD-10: I82.0). This registry contains diagnostic codes from all hospital discharges in Sweden since 1964 and from outpatient visits in specialized care since 2001.7Bengtsson B. et al.Scand J Gastroenterol. 2020; 55: 1205-1210Crossref PubMed Scopus (23) Google Scholar By manual chart review, a diagnosis of BCS in the registry had a positive predictive value of 93%.6Åberg F. et al.Clin Gastroenterol Hepatol. 2022; Google Scholar Here, we defined the start of follow-up (baseline) as 90 days after the date of BCS and excluded patients and control subjects meeting any of the following criteria before baseline: emigration from Sweden, death, liver transplantation, or previous HCC (Supplementary Figure 1). The lag period was introduced to exclude cases where HCC was likely present already at the date of BCS diagnosis. The primary outcome was incident HCC. The positive predictive value of a diagnosis of HCC in the National Patient Registry has been estimated to be 91% if combined with a chronic liver disease (eg, BCS).7Bengtsson B. et al.Scand J Gastroenterol. 2020; 55: 1205-1210Crossref PubMed Scopus (23) Google Scholar Because we suspected the incidence of HCC to be lower than previously reported, we defined HCC by ICD codes in the National Patient Registry, the Swedish Cancer Registry, and the Causes of Death Registry, to maximize the sensitivity (Supplementary Table 1). Follow-up was until the date of HCC, death, emigration from Sweden, liver transplantation, or December 31, 2016. The cumulative incidence of HCC was calculated while accounting for the competing risks of non-HCC death or liver transplantation (Supplementary Table 1).8Austin P.C. et al.Circulation. 2016; 133: 601-609Crossref PubMed Scopus (1015) Google Scholar Moreover, we analyzed the risk of HCC stratified for the presence of cirrhosis at baseline (defined as ICD coding for cirrhosis, ascites, esophageal varices, hepatorenal syndrome, or liver encephalopathy) (Supplementary Table 1). The study was approved by the regional ethics committee of Stockholm (protocol number 2017/1019-31/1). We identified 406 patients with BCS and 3883 matched control subjects who were followed for a median of 5.4 (interquartile range, 2.0–11.0) and 9.0 years (interquartile range, 4.1–14.1), respectively. The median age at baseline was 56 years and 42% were men in both groups. During follow-up, 7 persons developed HCC: 3 control subjects (0.08%) and 4 patients with BCS (0.99%). Patients with BCS had a higher incidence of HCC (1.3 per 1000 person-years; 95% confidence interval [CI], 0.5–3.6) compared with control subjects (0.1 per 1000 person-years; 95% CI, 0.0–0.2), corresponding to a hazard ratio of 11.9 (95% CI, 2.6–53.3). The cumulative incidence of HCC in patients with BCS was 0.57% at 5 years and 2.31% at 20 years (Table 1). In the 4 patients who developed HCC, the median age was 44 years at baseline (range, 39–61) and 56 years at the time of HCC (range, 50–63). The median time to HCC for these 4 patients was 7.5 years (range, 2.1–19.7). Of the 4 patients, 3 had cirrhosis at baseline and all developed cirrhosis before HCC. Among 77 (19.0%) patients with BCS who had a previous record of cirrhosis before baseline, the incidence of HCC was 7.3 per 1000 person-years (95% CI, 2.4–22.7) and the cumulative incidence 3.11% (95% CI, 0.58–9.64) at 5 years and 7.58% (95% CI, 1.56–20.18) at 20 years. In 329 (81.0%) patients with BCS without cirrhosis at baseline, 1 developed HCC after 19.7 years of follow-up, corresponding to an incidence of 0.4 per 1000 person-years (95% CI, 0.1–2.7) and a cumulative incidence at 20 years of 1.39% (95% CI, 0.12–6.58) (Table 1). BCS, Budd-Chiari syndrome; CI, confidence interval. The positive predictive values of our exposure and outcome definitions are high,6Åberg F. et al.Clin Gastroenterol Hepatol. 2022; Google Scholar,7Bengtsson B. et al.Scand J Gastroenterol. 2020; 55: 1205-1210Crossref PubMed Scopus (23) Google Scholar but misclassification bias can still exist. However, this limitation is more likely to lead to false-positive findings of HCC, which is why an overestimation of the risk of HCC in our analysis cannot be ruled out. Our data show that HCC is rare in unselected patients with BCS, with an absolute risk of 0.6% 5 years after BCS diagnosis and 2.3% at 20 years, corresponding to an excess risk at 20 years of 2.2% compared with the general population. In contrast, biopsy-proven alcohol-related liver disease and nonalcoholic fatty liver disease are associated with 20-year excess risks of 4.9% and 2.1%, respectively.9Hagstrom H. et al.Clin Gastroenterol Hepatol. 2022; 20: 918-929Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar,10Simon T.G. et al.Hepatology. 2021; 74: 2410-2423Crossref PubMed Scopus (29) Google Scholar However, these patients are not recommended universal screening for HCC, unless cirrhosis is present. Cirrhosis preceded HCC in all patients with BCS and no patient developed HCC before 50 years of age. In conclusion, screening for HCC may be considered in patients with BCS and concomitant cirrhosis aged 50 or more, but may not be motivated in other patients.